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Cellular and Molecular Biology

Effects of mitotically active polyploid giant cancer cells on chemoresistance through interaction with cancer-associated fibroblasts

British Journal of Cancer (2025)Cite this article

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Abstract

Background

Polyploid giant cancer cells (PGCCs), characterized by enlarged or multiple nuclei, have long been considered non-proliferative and hallmarks of high malignancy. However, their functional contribution to tumor progression remains unclear.

Methods

We identified and characterized a subset of mitotically active (MA)-PGCCs in human oral squamous cell carcinoma specimens and cell lines. Mitotic activity and cell cycle was assessed using immunofluorescence, time-lapse microscopy and FUCCI. We evaluated the interactions between MA-PGCCs and cancer-associated fibroblasts (CAFs), focusing on transforming growth factor-beta (TGF-β) signaling. Chemoresistance to 5-fluorouracil (5-FU) was analyzed using cell viability assays.

Results

MA-PGCCs exhibited both bipolar and multipolar mitosis, generating heterogeneous progeny that contributed to genomic instability. These cells increased the number of CAFs with elevated TGF-β expression, promoting epithelial-mesenchymal transition (EMT) and enhancing resistance to 5-FU. Mechanistically, enhanced reactive oxygen species in MA-PGCCs upregulated urokinase-type plasminogen activator (uPA) and its receptor uPAR, promoting plasmin-mediated activation of TGF-β secreted from adjacent CAFs. Upregulation of TGF-β receptors in MA-PGCCs further amplified TGF-β signaling, accelerating EMT.

Conclusions

Our findings identify MA-PGCCs as a proliferative subpopulation that promotes EMT and chemoresistance through a TGF-β-uPA/uPAR feedback loop. Targeting this pathway may offer a novel therapeutic strategy for the treatment of aggressive tumors enriched in MA-PGCCs.

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Fig. 1: Characterization of mitotic features of polyploid giant cancer cells (PGCCs) in human oral squamous cell carcinoma.
Fig. 2: Proliferation of SASMA-PGCCs via bipolar and multipolar cell division.
Fig. 3: SASMA-PGCC tumor contains dense collagen fibers and increase of fibroblasts.
Fig. 4: SASMA-PGCCs exhibit enhanced sensitivity to TGF-β signaling.
Fig. 5: Expressions of uPA and uPAR were upregulated in SASMA-PGCCs cells.
Fig. 6: Upregulation of uPA/uPAR in SASMA-PGCCs enhances resistance to 5-FU treatment.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank members of the Bioscience Education and Research Support Center (BERSC) of Akita University for technical assistance.

Funding

This work was supported by JSPS KAKENHI grants (23K24158, 25K02514 to M. Tanaka), Takeda Science Foundation grants (to M. Tanaka and G. Itoh), a Research Grant from the Princess Takamatsu Cancer Research Fund (19-25123 to M. Tanaka), Advanced Research Grant from the Dean of the Graduate School of Medicine, Akita University (G. Itoh), the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging and Cancer, Tohoku University (G. Itoh), and the Student Assistant of Center for Physician Scientist Training in Akita University (to K. Kanetaka).

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Authors and Affiliations

  1. Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan

    Go Itoh, Yuma Fukushi, Kurara Takagane, Sei Kuriyama & Masamitsu Tanaka

  2. Department of Life Science, Faculty and Graduate School of Engineering and Resource Science, Akita University, Akita, Japan

    Yuma Fukushi

  3. Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan

    Keisuke Kanetaka & Akiteru Goto

  4. Department of Otorhinolaryngology and Head-and-Neck Surgery, Akita University Graduate School of Medicine, Akita, Japan

    Hitomi Suzuki & Yohei Kawasaki

  5. Department of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagi, Japan

    Kenji Iemura & Kozo Tanaka

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Contributions

Conceptualization: GI and MT conceived the study and defined the research questions. Experiments and Investigation: GI, YF, KT1, KK, HS, YK, SK, AG, and MT conducted the experiments, collected data, and performed the necessary investigations. Methodology (Material Support): YK, KI, and KT2 provided material support, including the preparation of reagents, and assisted with experimental setup. Analysis and Interpretation of Data: GI, YF, and YK performed data analysis, with KK and AG leading the tumor tissue analysis using QuPath software. Writing—Original Draft: GI wrote the first draft of the manuscript, incorporating all contributions from co-authors. Writing—Review and Editing: MT critically reviewed and edited the manuscript. * KT1: Kurara Takagane and KT2: Kozo Tanaka.

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Correspondence to Masamitsu Tanaka.

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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. This study was approved by the Akita University Ethics Committee (approval number a-1-3175, Akita, Japan).

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Itoh, G., Fukushi, Y., Takagane, K. et al. Effects of mitotically active polyploid giant cancer cells on chemoresistance through interaction with cancer-associated fibroblasts. Br J Cancer (2025). https://doi.org/10.1038/s41416-025-03317-6

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